This invention relates to the use of substituted benzyllactobionamides as smooth muscle cell proliferation inhibitors and as therapeutic compositions for treating diseases and conditions which are characterized by excessive smooth muscle proliferation such as restenosis.
All forms of vascular reconstruction such as angioplasty and vein bypass procedures effect a response to injury that ultimately leads to smooth muscle cell (SMC) proliferation and subsequently, deposition of profuse amounts of extracellular matrix (Clowes, A. W.; Reidy, M. A. J. Vasc. Surg 1991, 13, 885). These events are also central processes in the pathogenesis of atherosclerosis (Raines E. W.; Ross R. Br. Heart J. 1993, 69 (Supplement), S. 30) as well as transplant arteriosclerosis (Isik, F. F.; McDonald, T. O.; Ferguson, M.; Yamanaka, E.; Gordon Am. J. Pathol. 1992, 141, 1139). In the case of restenosis following angioplasty, clinically relevant solutions for controlling SMC proliferation through pharmacological intervention have remained elusive to date (Herrman, J. P. R.; Hermans, W. R. M.; Vos, J.; Serruys P. W. Drugs 1993, 4, 18 and 249). Any successful approach to selective SMC proliferation inhibition must not interfere with endothelial cell repair or the normal proliferation and function of other cells (Weissberg, P. L.; Grainger, D. J.; Shanahan C. M.; Metcalfe, J. C. Cardiovascular Res. 1993, 27, 1191).
The glycosaminoglycans heparin and heparan sulfate are endogenous inhibitors of SMC proliferation, yet are able to promote endothelial cell growth (Castellot, J. J. Jr.; Wright, T. C.; Karnovsky, M. J. Seminars in Thrombosis and Hemostasis 1987, 13, 489). However, the full clinical benefits of heparin, heparin fragments, chemically modified heparin, low molecular weight heparins, and other heparin mimicking anionic polysaccharides may be compromised due to other pharmacological liabilities (excessive bleeding arising from anticoagulation effects, in particular) coupled with heterogeneity of the various preparations (Borman, S. Chemical and Engineering News, 1993 Jun. 28, 27).
U.S. Pat. No. 5,296,588, U.S. Pat. No. 5,336,765, and EP 550106A1 describe an improved process of preparing N-substituted aldonamides. U.S. Pat. No. 5,310,542 and EP 551675-A1 also describe glycosides (specifically aldobionamides) being used in oral hygiene compositions to act as antimicrobial agents and inhibit formation and/or growth of bacteria responsible for dental plaque. U.S. Pat. No. 2,752,334 describes a process of preparing N-substituted lactobionamides and their use as emulsifying agents (specially for cheese) and antimycotic agents. The compounds of the present invention differ in that the compounds of this invention (a) are acetylated or sulfated benzyllactobionamides, (b) have substituents on the aromatic core that are different, and (c) are being used as smooth muscle cell antiproliferatives.
EP 312086 A2 and EP 312087 A2 describe polysulfate ester(s) of bis-aldonic acid amide derivatives as antiinflammatory and antithrombotic agents. The compounds of the present invention differ in that the compounds (a) are being used as smooth muscle cell antiproliferatives, (b) are not dimeric in nature, and (c) contain no more than two contiguous sugar residues (disaccharide).
(Klein, U.; Mohrs, K.; Wild, H.; Steglich, W. Liebigs Ann. Chem. 1987, 485–489.) describes the use of peracetylated aldonamides to prepare 3-substituted pyrazoles. The compounds of the present invention differ in that the compounds (a) have substituents on the aromatic core that are different, (b) are not substituted at the benzylic position, (c) are being used as smooth muscle cell antiproliferatives, and (d) are not used as precursors to pyrazoles.
U.S. Pat. No. 5,498,775, WO 96/14324, and U.S. Pat. No. 5,464,827 describe polyanionic benzylglycosides or cylcodextrins as smooth muscle cell proliferation inhibitors for treating diseases and conditions that are characterized by excessive smooth muscle proliferation. β-Cyclodextrin tetradecasulfate has been described as a smooth muscle cell proliferation inhibitor and as an effective inhibitor of restenosis (Reilly, C. F.; Fujita, T.; McFall, R. C.; Stabilito, I. I.; Wai-si E.; Johnson, R. G. Drug Development Research 1993, 29, 137). U.S. Pat. No. 5,019,562 discloses anionic derivatives of cyclodextrins for treating pathological conditions associated with undesirable cell or tissue growth. WO 93/09790 discloses antiproliferative polyanionic derivatives of cyclodextrins bearing at least 2 anionic residues per carbohydrate residues. Meinetsberger (EP 312087 A2 and EP 312086 A2) describes the antithrombotic and anticoagulant properties of sulfated bis-aldonic acid amides. U.S. Pat. No. 4,431,637 discloses polysulfated phenolic glycosides as modulators of the complement system. The compounds of the present invention differ from all of the prior art in that the compounds (a) are benzyllactobionamides which bear no structural resemblance to heparin or sulfated cyclodextrins, (b) are compounds which are not dimeric in nature, (c) contain no more than two contiguous sugar residues (disaccharide), and (d) are of defined structure.
WO 9614325 discloses acylated benzylglycosides as smooth muscle cell proliferation inhibitors. The compounds of the present invention differ in that (a) the saccharide backbone is different, (b) the open chain core has preparation advantages over the cyclic array, and (c) the substituents on the carbohydrate backbone are different.
(Zehavi, U.; Herchman, M. Carbohyd. Res. 1986, 151, 371) discloses 4-carboxy-2-nitrobenzyl 4-O-α-D-glucopyranosyl-β-D-glucopyranoside which is attached to a polymer for study as an acceptor in the glycogen synthase reaction. The compounds of the present invention differ from those of the Zehavi disclosure in that (a) the substituents on the benzyl groups are different and (b) the use (smooth muscle antiproliferation) is different.